1. Field of the Invention
The present invention relates to a pharmaceutical preparation for percutaneous absorption comprising a substrate having provided thereon an adhesive layer containing a relatively hydrophilic drug and more particularly, to a preparation for percutaneous absorption which is used as a plaster having a high percutaneous absorption of a drug over long periods of time and having a difficultly decreasing adhesiveness over long periods of time.
2. Statement of the Prior Art
Pharmaceutical preparations for percutaneous absorption. have many advantages as compared to oral administration in that they can avoid liver metabolism, can maintain blood concentration of a drug in a definite range over long periods of time, can be used in a simple fashion, etc. Among preparations for percutaneous absorption, a plaster is an extremely desirable preparation since a dose can be set in a definite range, a plaster itself has a high adhesive force, one has a low feeling of foreign matter with a plaster upon use and there is no chance of getting clothes dirt.
However, the skin plays a role of protecting the living body to prevent invasion of a foreign matter into the body and hence, in many cases, it is difficult to percutaneously administer a drug in a sufficient dose into the body. Therefore, it is necessary to take measures such as increasing an area to be applied, increasing an amount of a drug to be permeated per unit area, and the like. However, an excessively increased area to be applied results in inconvenience upon use or a high feeling of foreign matter so that practicability is damaged. It is thus automatically limited to increase the area. On the other hand, in order to increase an amount of a drug to be permeated per unit area, there are many proposals that a drug concentration in a base or an adhesive layer is increased, an absorption enhancer is added, etc. An increased concentration of a drug in a base is an effective means since drug permeability can be maintained in a high level over long periods of time. However, the solubility of a hydrophilic drug is low in a general adhesive so that an increase in drug concentration in a base results in crystallization on the surface or in the inside of a base. Formation of drug crystals results in a serious decrease in adhesiveness and in many hydrophilic drugs, releasability from a base is also markedly reduced. That is, many hydrophilic drugs encounter serious problems that a drug concentration in a base is increased only with difficulty, and there is no adhesive capable of maintaining these drugs in a high concentration.
In order to solve the foregoing problems, it is proposed in Japanese Patent Application Laid-Open No. 61-260028 to use poly-N-vinyl-lactam or a copolymer of N-vinyl-lactam as one component of the therapeutically active compound-releasing system using as a base an adhesive having physical properties of a rubber. It is taught that these components in a base of rubber type adhesive prevent from crystallization a therapeutically active compound in the therapeutically active compound-releasing system or at least greatly retarding the crystallization.
Where the rubber type adhesive is used as a base, however, there is a poor compatibility between the rubber type adhesive and poly-N-vinyl-lactam or a copolymer of N-vinyl-lactam so that stability of the resulting matrix is deteriorated with passage of time. Unless the matrix is stable with passage of time, the applicability and releasability of a plaster are also unstable, and these situations are serious problems as a drug. Furthermore, in the case of a hydrophilic drug, its solubility in a rubber type adhesive is extremely low so that the rubber type adhesive is not suited for increase a drug concentration, either.
Turning to Japanese Patent Application Laid-Open No. 60-185713, there is proposed a method which comprises applying a solution of adhesive containing a drug on one surface of a substrate and crystallizing crystals of the drug during a subsequent drying step thereby to disperse the crystals in a base in a finely divided particulate state. However, many drugs have an extremely low dissolution rate of a drug in a base from a crystalline state. Therefore, this method cannot be generalized for all drugs.
Topical plasters using, e.g., Piroxicam, are described in Japanese Patent Application Laid-Open Nos. 63-159318 and 3-109327. However, drug concentrations in solid preparations found in these examples are as low as 1% or less and 3% or less, respectively. It is thus difficult to maintain a necessary amount of the drug in a base over long periods of time.
It is particularly advantageous to add an absorption enhancer, since the enhancer improves a drug permeability. For example, Japanese Patent Application Laid-Open No. 61-172833 indicates that by using phospholipid as an absorption enhancer in combination with a non-steroidal antiinflammatory agent in percutaneous administration, percutaneous absorption is increased. However, such an effect is not recognized with all drugs; a percutaneous absorption enhancing action of phospholipid is insufficient for, e.g., Piroxicam and hence, any sufficient therapeutic effect cannot be expected.